Advances in the Research of Natural Health Products as Main Stream Cancer Therapeutics

Natural health products (NHPs) are defined as natural extracts containing polychemical mixtures; they play a leading role in the discovery and development of drugs, for disease treatment. More than 50% of current cancer therapeutics are derived from natural sources. However, the efficacy of natural extracts in treating cancer has not been explored extensively. Scientific research into the validity and mechanism of action of these products is needed to develop NHPs as main stream cancer therapy. The preclinical and clinical validation of NHPs would be essential for this development. This review summarizes some of the recent advancements in the area of NHPs with anticancer effects. This review also focuses on various NHPs that have been studied to scientifically validate their claims as anticancer agents. Furthermore, this review emphasizes the efficacy of these NHPs in targeting the multiple vulnerabilities of cancer cells for a more selective efficacious treatment. The studies reviewed here have paved the way for the introduction of more NHPs from traditional medicine to the forefront of modern medicine, in order to provide alternative, safer, and cheaper complementary treatments for cancer therapy and possibly improve the quality of life of cancer patients.

History of Natural Health Products (NHPs) in Cancer

Natural health products (NHPs) and natural products (NPs) play a leading role in the discovery and the development of drugs for the treatment of human diseases. Traditional medicines in the Native American, Chinese, and Indian cultures have utilized numerous natural products, including dozens of spices and plant extracts. Scientific research into the validity of these traditional products has shown that many do indeed have potent anticancer effects [1, 2]. An extract from the Mayapple, Podophyllum peltatum, was traditionally used by Native Americans to combat skin cancers and other malignant neoplasms, as well as a host of other ailments. The major component of this extract was podophyllotoxin, which was the first in a series of effective anticancer agents called podophyllins. Likewise, numerous natural products used in traditional Indian Ayurvedic medicine have been shown to have strong anti-inflammatory and anticancer properties.

Curcumin, the active ingredient in turmeric, has been widely studied for its anticancer properties. Turmeric (Curcuma longa), itself, was widely used in Ayurvedic medicine and the therapeutic benefits, which are now attributed to the presence of curcumin, include the ability to suppress tumor growth in a wide variety of cancer types. A total of 27 anticancer drugs from 1940 to 2010 were obtained from natural sources, for instance actinomycin D, paclitaxel, and vincristine, now one of the most commonly used chemotherapy agents in cancer treatment, while topotecan HCl, dexamethasone, etoposide, and even tamoxifen are mimics of natural products (Figure 1). Camptothecin, found in extracts from Camptotheca acuminate and used in traditional Chinese medicine, has been found to have antitumor activity and its derivatives, topotecan, and irinotecan are routinely used to treat ovarian and colon cancers .

Figure 1 

Sources of anticancer drugs from the 1940s to 2010. Natural product (N), derived from a natural product, usually a synthetic derivative (ND). Natural product “Botanical” (NB); natural product mimic (NM); totally synthetic drug (S) made by total synthesis, but the pharmacophore is/was from a natural product (S).

The discovery of the anticancer activities of so many traditional medicines and natural products has been supported by scientific evidence and validation. This was in part successful due to the initiation of the Cancer Chemotherapy National Service Center (CCNSC) in 1955, by the National Cancer Institute (NCI). The mandate of this program was to screen for antitumor agents on a larger scale by establishing a strict standardized protocol for testing potential anticancer compounds .

Since the 1980s, research into the anticancer effects of natural products has yielded many promising results. For example, resveratrol, a polyphenol present in grapes, shows potential as both a preventative and an antitumor agent . Similarly, piperlongumine, extracted from Piper longum, selectively induces reactive oxygen species in cancerous cells, leading to apoptotic cell death [9]. In the 1980s, Bagshawe et al. developed a novel use for natural products, the antibody-directed enzyme-prodrug therapy (ADEPT). This technique used tumor-specific antibodies bound to an enzyme that would convert noncytotoxic prodrugs into their cytotoxic forms once in contact with the tumor. Many natural products were successfully used as prodrugs, including doxorubicin and Taxol . These earlier studies have paved the way for the introduction of more NHPs from traditional medicine to the forefront of modern medicine. The scientific validation of these NHPs in terms of their efficacy, safety, and mechanism of actions will seal their position in modern medicine, especially in the field of cancer research and therapy.

Current Trends in NHP Research and Cancer
Even with all the incoming evidence, herbal drugs and other NHPs and NPs are usually shunned during systemic chemotherapy because of herb-drug interaction and exaggeration of chemotherapy-related toxicity. Current research is focused on the development of new and more effective chemotherapeutic agents that have little to no associated toxicity to the patient. Lately, this focus has been centered on NHPs and herbal formulations, mainly in the form of plants and other biological sources around the world. NHPs have been used for centuries by a variety of cultural backgrounds for a great number of illnesses; some of which continually provide new medicinal applications and intriguing anecdotal evidence, which merits further investigation. Today, there are numerous natural health products that fall under the umbrella of traditional medicine, such as the Indian herbs Tulsi (Ocimum sanctum), Neem (Azadirachta indica), and Ashwagandha (Withania somnifera), commonly known as Indian ginseng or winter cherry. These herbs have shown an incredible diversity of treatments for diseases in both ancient and modern times as well. Ayurvedic medicine has been very informative in the introduction of numerous NHPs. Tulsi, also referred to as “Holy Basil,” has in past decades been studied for its many health benefits, which includes but is not limited to treatments for bronchitis, pain, malaria, asthma, arthritis, cancer, diabetes, and numerous microbial infections . One study claims that it is primarily the phenolic compound, eugenol, to which the health benefits of Tulsi are owed ; however more recent research suggests that there is an additional range of compounds at work, including the phytochemicals rosmarinic acid, apigenin, myretenal, luteolin, β-sitosterol, and carnosic acid; all of which have been shown to be valuable in the reduction of chemically induced cancers through initiating apoptosis and maintaining antioxidative and antiangiogenic effects. On the same page, Neem leaves have been shown to possess a strikingly similar range of

pharmacological effects to Tulsi and in one study is referred to as a “living pharmacy” in itself . The benefits of Neem range from reductions in inflammation, microbial infection, progression of diabetes, oxidative stress, cancer proliferation, and tumor development, indicating chemopreventive benefits. Some of the active compounds within Neem are Azadirone, Nimbidin, Nimbolide, and the Polysaccharides GIa and GIb. Ashwagandha has been a staple in traditional Indian medicine for decades and has been widely used, owing to the various properties that have been attributed to it. Ashwagandha is proposed to have antioxidant, anti-inflammatory, anticancer, antistress, and adaptogenic properties . The extracts of this plant have been studied intensely to validate the claims that have been the backbone of its use in ayurvedic medicine. A recent study in 2013 showed the efficacy of Withania extract against metastatic breast cancer. The ethanolic extract of this plant was efficient in preventing the invasion of breast cancer cells in a spheroid invasion assay, while inhibiting the metastasis of breast tumors to the lungs and lymph nodes in animal models . In Phase II clinical studies, this herb was shown to promote “general well-being of patients,” when used in combination with chemotherapy, as well as enhance the cytotoxicity of chemotherapy in breast cancer patients. This combination treatment led to an increase in the quality of life of the breast cancer patients in this study.

Another example of an NHP that has been used for centuries is the extract of dandelion, a perennial weed known for its curative properties. The dandelion species have been used in many traditional and modern herbal medicinal systems and this use has been documented all across the continents. Various parts of this plant have been used in the treatment of different ailments, with the root being used in gastrointestinal diseases and the leaves as a diuretic and digestive stimulant. The whole plant has been taken as a cure for hepatitis and anorexia as well, although some of the claims associated with this weed have gone unsubstantiated . Some preclinical research on dandelion has introduced this plant with numerous properties to the scientific community. Research has shown the anti-inflammatory, prebiotic, antiangiogenic, and antineoplastic properties of dandelion root . However, some studies do not agree with others, leading to the publication of conflicting reports on this NHP. More recently, studies have shown selective efficacy of dandelion root extract (DRE) against several cancer cell types in a dose and time dependent manner. The investigation of the mechanism of action of dandelion root extract in cancer cells is under study, with focus on the identification of the possible apoptotic pathway in which this extract is selective to cancer cells. It has been shown that DRE targets the death-receptor mediated extrinsic pathway of apoptosis and its mechanism is dependent on the activation of caspase-8 . Overwhelming scientific evidence with the aforementioned NHPs are paving the way for other NHPs, especially in cancer treatment and introducing these compounds and products as safe alternatives and effective contenders in the fight against cancer.

Natural Health Products in Inflammation and Inflammatory Response in Cancer

It is well-known that the inflammatory response is vital in living organisms for their protection against foreign matter. Inflammation more commonly occurs in cases of infection and injury (acute inflammation), but in certain situations, a more persistent, deregulated, and maladaptive inflammation (chronic inflammation) can arise. This chronic form of inflammation is usually associated with chronic diseases like cancer, where there is exacerbation of the disease, due to the prolonged inflammatory response. This would lead to increased proliferation of the cancer cells, increased angiogenesis, and promotion of metastatic capabilities , making chronic inflammation a hallmark of neoplastic transformation . Unlike acute inflammation, there is not much known about the processes and molecular pathways associated with chronic inflammation ; however, there are anti-inflammatories available that might be able to target the inflammation and possibly the molecular pathways involved in order to reduce the extent of inflammation and possibly the unwanted effect of inflammation in chronic diseases, like cancer. One of the most common examples for the role of inflammation in cancer progression has been the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 specific inhibitors, to reduce the risk of developing some cancers and preventing the mortality associated with those cancers . These NSAIDs and COX-2 inhibitors act by interfering with eicosanoid signaling and metabolism, suppressing the formation of tumors and acting as antioxidants and antiangiogenics.

It has been found that there is a shared pathology between cancer and inflammatory diseases, which is displayed in the gene expression signatures for cancer and those for inflammatory diseases . These findings suggest that targeting the inflammatory response is a potential way to target different forms of cancer. To combat unwarranted inflammation, anti-inflammatories like aspirin, ibuprofen, and prednisone are most commonly used, despite their side effects . Alternatively, natural health products are used to heal a variety of ailments including inflammation in a safe and effective manner. This prompts continual research into the mechanism of natural anti-inflammatories as well as the discovery of new natural therapies. Several phytochemicals, including curcumin from turmeric and resveratrol from grapes, are used partly due to their anti-inflammatory activity. They inhibit inflammation by suppressing the activity of NF-κB and possible STAT-3 .

Long pepper or Piper longum L. has been used as both a spice and a therapy for a number of centuries. Historically, it was used as a topical treatment for muscle inflammation but has shown efficacy in a number of diseases and conditions including diabetes, cancer, and obesity without having any toxic effects . More recently, the plant has been studied as an anti-inflammatory agent for carrageenan-induced paw edema in rats. In the study, researchers found a significant decrease in paw inflammation of rats treated with long pepper indicating that long pepper suppressed acute and subacute inflammation . In addition to this study, other work has been done on piperlongumine, an important component of the long pepper fruit, as a therapy against atherosclerosis. This study found that the anti-inflammatory and antiplatelet aggregation properties of piperlongumine prevented artherosclerotic plaque formation in mice, proving it to be a possible therapy for this inflammatory disease . Furthermore, in vitro studies in various cancer cell lines showed the anticancer effect of piperlongumine in these cells, where it was shown that this compound was able to target the oxidative stress response of these cells, increase the levels of reactive oxygen species (ROS), and activate the expression of several key proapoptotic proteins. This anticancer effect was confirmed in in vivo models of breast adenocarcinoma . Piperlongumine represents one of the compounds present within long pepper that provides the anti-inflammatory response from this plant; however the effect of this compound alone is significantly less than the whole plant extract in reducing inflammatory response .

In addition to long pepper and piperlongumine, a natural compound found in grapes, peanuts, and berries known as resveratrol (3,4′,5-trihydroxystilbene) is a fat soluble compound that has also shown anti-inflammatory potential. Researchers became interested in elucidating the potential health benefits of resveratrol when it was reported to be present in red wine, which had previously been shown to reduce coronary heart disease by 20–30% . It has been found that resveratrol can have a direct effect on the immune response of the body and thus can be used as an immunomodulator in patients with inflammatory diseases . More specifically, resveratrol suppresses the expression of inflammatory biomarkers like TNF, COX-2, iNOS, and CRP, preventing inflammation . Additionally, resveratrol has been shown to impede the activity of at least one type of matrix metalloproteinase enzymes which assist the invasion of normal tissue by cancer cells. The anti-inflammatory properties of resveratrol have also been demonstrated in vitro. Studies are inconclusive on whether or not high intakes of resveratrol are effective in protecting against and preventing cancer in humans ; however, due to the ability of this compound to act as a potential therapeutic measure for cancer, it is essential to pursue further studies on this NHP. As noted earlier, due to the low bioavailability of resveratrol in humans, studies suggest that even high intakes of resveratrol may not result in the same anticancer effectiveness that was demonstrated in cell culture .

Dandelion extracts have been found to have anti-inflammatory activity in some cancer cells . In a study by Jeon and colleagues in 2008, an ethanolic extract of the whole plant was shown to possess anti-inflammatory properties. This extract led to the downregulation of the production of NO and COX-2 in activated macrophage cells .

These findings suggest a great potential for NHPs with anti-inflammatory activity in the fight against cancer. The ability of these NHPs to target multiple pathways in inflammation and in cancer progression provides a potentially more efficacious way to selectively target cancer cells.

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